The triggering mutation JAK2 V617F plays a key position in the pathogenesis of essential thrombocythemia, polycythemia vera, and primary myelofibrosis. However, the proapoptotic proteins involved in JAK2 inhibitioninduced apoptosis remain uncertain. In this study, we demonstrate that JAK2 inhibitioninduced apoptosis correlated with upregulation of the nonphosphorylated c-Met Inhibitors kind of the BH3 only protein Bim in hematopoietic cell lines showing JAK2 mutations. Knockdown of Bim significantly inhibited apoptosis induced by JAK2 inhibition, which was reversed by the BH3 mimetic adviser ABT 737. In addition, ABT 737 enhanced the apoptosis induced by JAK2 inhibition in SET 2 cells and JAK2 V617F HEL. The combination of JAK inhibitor I and ABT 737 paid down the amount of erythroid colonies derived from CD34 cells isolated from JAK2 V617F polycythemia vera patients better than either drug alone. These data suggest that Bim is a critical effector molecule in JAK2 inhibition induced apoptosis and that targeting this apoptotic pathway could be a new therapeutic strategy for patients with activating JAK2 mutations. :2901 2909 Introduction Myeloproliferative disorders are clonal hematopoietic conditions characterized by the surplus production of just one or more lineages of mature blood Infectious causes of cancer cells resulting in problems of organomegaly, thrombosis, and hemorrhage. 1 Recently, a somatic activating mutation in Janus kinase 2, a non-receptor tyrosine kinase, was discovered in patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis. 2 6 A valine to phenylalanine substitution at position 617 of JAK2 in the pseudokinase area may be the most frequent mutation, occurring in more than 95% of PV cases and in about 50-pint of patients with ET and PMF. 7 Other variations, for example T875N and K539L, have already been recognized natural product libraries in a small part of PV people and in a megakaryoblastic leukemia cell line, CHRF 288 11 cells, respectively. 7 Traditional treatment for PV, ET, and PMF with cytoreductive chemotherapy or phlebotomy is not curative and does not decrease the risk of clonal evolution into myelodysplastic syndrome and acute leukemia. Ergo, inhibition of mutant JAK2 can be a novel approach in the treatment of PV and other MPDs harboring JAK2 versions. Various JAK inhibitors are currently under development and/or investigation in stage 1 and 2 clinical trials. Nevertheless, initial reports from a clinical trial with one such JAK chemical, INCB018424, indicated that one fourth of patients developed severe, though reversible, hematologic toxicities with initial dosing regimens. Moreover, just a modest reduction in JAK2 V617F allele burden was seen in peripheral blood and bone marrow from higher level myelofibrosis patients. A phase 1 study of XL019, still another JAK2 inhibitor, shows that reversible peripheral neuropathy may appear at high doses.